The search for genetic markers associated with complex diseases is ongoing. Genomewide scanning studies with SNP arrays continue to highlight the ApoE region as the most important area for investigation in the study of Alzheimer's disease (Coon et al., J. Clin. Psychiatry 68: 613-8 (2007); Li et al., Arch. Neurol. 65: 45-53 (2007)).
The ApoE 4 isoform has previously been strongly associated with increased risk of developing late-onset Alzheimer's disease. (Pericak-Vance et al., Am. J. Hum. Genet. 48, 1034-50 (1991); Martin et al., 2000, U.S. Pat. No. 6,027,896 to Roses, et al., U.S. Pat. No. 5,716,828 to Roses et al.) The relationship is dose dependent (Yoshizawa et al., 1994; Schellenberg, 1995). That is to say, a carrier of two ApoE 4 alleles is more likely to develop late-onset Alzheimer's disease (LOAD) than a carrier of only one ApoE 4 allele, and at an earlier age (Corder et al., Science 261, 921-3 (1993)).
Nevertheless, E4 alleles only account for roughly 50% of hereditary Alzheimer's disease. One explanation is that ApoE 4 is merely serving as a surrogate marker for something in linkage disequilibrium nearby. Alternatively, considering the recent discovery of a mechanistic role for ApoE 4 in mitochondrial toxicity, the negative effects of ApoE 4 may be abrogated or exacerbated by another gene product encoded nearby (Chang et al., 2005).
As ApoE status is also associated with risk for coronary artery disease and likely also a host of other diseases and disorders, the implications of the study of the ApoE region are not limited to Alzheimer's disease, but are potentially far-reaching (Mahley et al., Proc. Natl. Acad. Sci. USA 103: 5644-51 (2006)). More broadly, the examination of variant sequences for processes or pathways surrounding genes in linkage disequilibrium with other genetic regions known to be involved in complex disease processes will provide valuable information in deciphering the mechanisms of those diseases.